Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cannabinoid Receptor Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed2004

Selective antiepileptic effects of N-palmitoylethanolamide, a putative endocannabinoid.

PURPOSE: The purpose of this study was to determine whether N-palmitoylethanolamide (PEA), a putative endocannabinoid, would be effective against kindled amygdaloid seizures. For a comparison with earlier work, we also tested the effectiveness of PEA against pentylenetetrazol (PTZ)-induced convulsions. METHODS: Kindling electrodes were implanted bilaterally in the amygdala in 32 Long-Evans rats. After the kindling of generalized (stage 5) seizures, the effects of PEA administration [i.p.; 1, 10, 100 mg/kg in dimethylsulfoxide (DMSO)] were evaluated for anticonvulsant activity. PEA (40 mg/kg, i.p. in DMSO) also was tested for anticonvulsant activity against PTZ-induced convulsions (75 mg/kg, i.p.). RESULTS: After i.p. administration of PEA, kindled rats displayed an increased latency to clonus at the 1-mg/kg dose. No other dose-dependent effects were noted. When tested against PTZ-induced convulsions, PEA protected against tonic convulsions and prolonged the latency between convulsive episodes. CONCLUSIONS: PEA produces antiepileptic effects, but does not completely suppress seizures. The mechanism of action of PEA remains to be defined.

Amides↗
PubMed2001

Cannabinoids and pain.

Cannabinoids have been used to treat pain for many centuries. However, only during the past several decades have rigorous scientific methods been applied to understand the mechanisms of cannabinoid action. Cannabinoid receptors were discovered in the late 1980s and have been found to mediate the effects of cannabinoids on the nervous system. Several endocannabinoids were subsequently identified. Many studies of cannabinoid analgesia in animals during the past century showed that cannabinoids block all types of pain studied. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, independent of any actions on the motor systems. Spinal, supraspinal and peripheral sites of cannabinoid analgesia have been identified. Endocannabinoids are released upon electrical stimulation of the periaqueductal gray, and in response to inflammation in the extremities. These observations and others thus suggest that a natural function of cannabinoid receptors and their endogenous ligands is to regulate pain sensitivity. The therapeutic potential of cannabinoids remains an important topic for future investigations, with previous work suggesting utility in clinical studies of cancer and surgical pain. New modes of delivery and/or new compounds lacking the psychotropic properties of the standard cannabinoid ligands offer promise for cannabinoid therapeutics for pain.

Analgesia↗
PubMed2005

VR1-mediated depressor effects during high-salt intake: role of anandamide.

This study was designed to test the hypothesis that increased sensitivity of blood pressure to anandamide (AEA), an endocannabinoid compound, occurs during high-salt intake, which can be blocked by a selective vanilloid receptor 1(VR1) antagonist, capsazepine (CAPZ). Intravenous administration of a metabolically stable analog, methanandamide (MethA), dose-dependently decreased mean arterial pressure (MAP) in conscious rats fed a high-sodium diet (HS) for 3 weeks but it had a minimal effect in normal sodium (NS)-treated rats. The MethA-induced decrease in MAP was significantly attenuated but not abolished by CAPZ, or a selective cannabinoid receptor 1 (CB1) antagonist, SR141716A, administered separately in HS-treated rats. The MethA-induced depressor effect was prevented by the combined administration of CAPZ and SR141716A in HS-treated rats. Likewise, administration of capsaicin, a selective VR1 receptor agonist, dose-dependently decreased MAP in both HS- and NS-treated rats. The depressor effect of capsaicin was more profound in HS-treated rats, which was prevented by CAPZ. Western blot showed that expression of VR1 but not CB1 in mesenteric arteries was increased in HS-treated compared with NS-treated rats. Therefore, these data show that: (1) HS upregulates mesenteric VR1 expression; (2) HS increases sensitivity of blood pressure to AEA; and (3) HS-induced enhancement of the depressor effect of AEA can be prevented only when both VR1 and CB1 receptors are blocked. These results indicate that AEA contributes to the prevention of salt induced increases in blood pressure via, at least in part, activating the VR1 receptor.

Animals↗
PubMed2006

Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain.

OBJECTIVE: To review the literature concerning the physiology of the endocannabinoid system, current drug development of cannabinoid agonists, and current clinical research on the use of cannabinoid agonists for analgesia. DATA SOURCES: Articles were identified through a search of MEDLINE (1966-August 2005) using the key words cannabis, cannabinoid, cannabi*, cannabidiol, nabilone, THC, pain, and analgesia. No search limits were included. Additional references were located through review of the bibliographies of the articles identified. STUDY SELECTION AND DATA EXTRACTION: Studies of cannabinoid agonists for treatment of pain were selected and were not limited by pain type or etiology. Studies or reviews using animal models of pain were also included. Articles that related to the physiology and pharmacology of the endocannabinoid system were evaluated. DATA SYNTHESIS: The discovery of cannabinoid receptors and endogenous ligands for these receptors has led to increased drug development of cannabinoid agonists. New cannabimimetic agents have been associated with fewer systemic adverse effects than delta-9-tetrahydrocannabinol, including recent development of cannabis medicinal extracts for sublingual use (approved in Canada), and have had promising results for analgesia in initial human trials. Several synthetic cannabinoids have also been studied in humans, including 2 cannabinoid agonists available on the international market. CONCLUSIONS: Cannabinoids provide a potential approach to pain management with a novel therapeutic target and mechanism. Chronic pain often requires a polypharmaceutical approach to management, and cannabinoids are a potential addition to the arsenal of treatment options.

Analgesics, Non-Narcotic↗
PubMed2005

Endocannabinoids and drug dependence.

Drug dependence is a chronically relapsing disorder, manifested as an intense desire for the drug, with impaired ability to control the urges to take the drug, even at the expense of serious adverse consequences. These behavioral abnormalities develop gradually during repeated exposure to a drug of abuse, and can persist for months or years after discontinuation of use, suggesting that this addiction can be considered a form of drug-induced neural plasticity. Many neurotransmitters, including gamma-aminobutyric acid (GABA), glutamate, acetylcholine, dopamine, serotonin and endogenous opioid peptides, have been implicated in the effects of the various drugs of abuse. Dopamine has been consistently associated with the reinforcing effects of most of them. There is, in addition, a growing body of evidence that the endogenous cannabinoid system might participate in the motivational and dopamine-releasing effects of several drugs of abuse. This review will discuss the latest advances on the mechanisms of cannabinoid dependence and the possible role of the endocannabinoid system in the treatment of addiction, not only to marijuana but also to the other common illicit drugs.

Alcoholism↗
PubMed1999

Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids.

In agreement with the highly lipophilic nature of (-)-delta9-tetrahydrocannabinol, all the endogenous ligands of cannabinoid receptors identified so far are derivatives of long chain fatty acids. N- Arachidonoylethanolamine (anandamide) and some of its polyunsaturated congeners have been found in mammalian brain and shown to activate the CB1 and, with a lower efficacy, CB2 cannabinoid receptor subtypes. More recently, 2-arachidonoylglycerol (2-AG), a widespread intermediate in the metabolism of phosphoglycerides, diacylglycerols and triglycerides, was also found to activate the cannabinoid receptors. The capability of palmitoylethanolamide, an anti-inflammatory metabolite, to activate CB2-like receptors is still being debated. Here we review: 1) the metabolic pathways suggested so far to underlie the biosynthesis and inactivation of anandamide and 2-AG, and 2) the current knowledge of the chemical bases for the interactions of anandamide and 2-AG with proteins of the endogenous cannabinoid system characterized so far, i.e. the CB1 and CB2 receptor subtypes, the membrane anandamide carrier , which facilitates anandamide diffusion into cells, and the enzyme fatty acid amide hydrolase , which catalyzes anandamide and, to a certain extent, 2-AG hydrolysis in vivo.

Animals↗
PubMed2002

Functional role for cannabinoids in respiratory stability during sleep.

STUDY OBJECTIVES: Serotonin, acting in the peripheral nervous system, can exacerbate sleep-related apnea, and systemically administered serotonin antagonists reduce sleep-disordered respiration in rats and bulldogs. Because cannabinoid receptor agonists are known to inhibit the excitatory effects of serotonin on nodose ganglion cells, we examined the effects of endogenous (oleamide) and exogenous (delta9-tetrahydrocannabinol; delta9THC) cannabimimetic agents on sleep-related apnea. DESIGN: Sleep architecture, respiratory pattern, and apnea expression in rats were assessed by polysomnography. A repeated measures, within-subjects, fully nested crossover design was used in which each animal was recorded on exactly 12 occasions. PARTICIPANTS: Eleven adult male Sprague-Dawley rats were instrumented for chronic polysomnography. INTERVENTIONS: Animals were recorded following intraperitoneal injection of various doses of delta9THC, oleamide, and serotonin, alone and in combination. MEASUREMENTS AND RESULTS: Our data show that delta9THC and oleamide each stabilized respiration during all sleep stages. With delta9THC, apnea index decreased by 42% (F=2.63; p=0.04) and 58% (F=2.68; p=0.04) in NREM and REM sleep, respectively. Oleamide produced equivalent apnea suppression. This observation suggests an important role for endocannabinoids in maintaining autonomic stability during sleep. Oleamide and delta9THC blocked serotonin-induced exacerbation of sleep apnea (p<0.05 for each), suggesting that inhibitory coupling between cannabinoids and serotonin receptors in the peripheral nervous system may act on apnea expression. CONCLUSIONS: This study demonstrates potent suppression of sleep-related apnea by both exogenous and endogenous cannabinoids. These findings are of relevance to the pathogenesis and pharmacological treatment of sleep-related breathing disorders.

Animals↗
PubMed2005

Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders.

Immune system responsiveness results from numerous factors, including endogenous cannabinoid signaling in immunocytes termed the "immunocannabinoid" system. This system can be an important signaling pathway for immune modulation. To assess the immunomodulating role of the cannabinoid 2 (CB2) receptor, we sought polymorphisms in the human gene, identified a common dinucleotide polymorphism, and investigated its effect on endocannabinoid-induced inhibition of T lymphocyte proliferation. The CB2 cDNA 188-189 GG/GG polymorphism predicts the substitution of glutamine at amino acid position 63 by arginine. T lymphocytes from CB2 188-189 GG/GG homozygotes had approximately twofold reduction of endocannabinoid-induced inhibition of proliferation compared with cells from CB2 188-189 AA/AA homozygotes. In GG/GG subjects, the reduced endocannabinoid inhibitory response was highly significant for N-arachidonylglycine and nearly significant for 2-arachidonylglycerol, and a specific CB2 receptor antagonist partially blocked these effects. Also, patients with autoimmune diseases had an increased prevalence of the homozygous GG/GG genotype. Collectively, these results demonstrate reduced endogenous fatty acid amide immunomodulatory responses in individuals with the CB2 188-189 GG/GG genotype and suggest that this CB2 gene variation may be a risk factor for autoimmunity. The results also support the proposition that the CB2 receptor may represent a novel pharmacological target for selective agonists designed to suppress autoreactive immune responses while avoiding CB1 receptor-mediated cannabinoid adverse effects.

Amino Acid Substitution↗
PubMed2006

Spinal modulation of calcitonin gene-related peptide by endocannabinoids in the development of opioid physical dependence.

Studies implicate endocannabinoids in the acute and chronic actions of opioid drugs, including the genesis of physical dependence. Previous evidence suggests that spinal release of calcitonin gene-related peptide (CGRP) and activation of its receptors contribute to opioid physical dependence. The release of CGRP at the spinal level is modulated by cannabinoid (CB1)-receptors. Thus, this study examined whether CB1-receptor activity mediates changes in CGRP underlying development of opioid physical dependence. Systemic morphine administration for 5-days elevated CGRP-immunoreactivity in the rat spinal dorsal horn. In situ hybridization of dorsal root ganglion (DRG) neurons revealed an increase in CGRP mRNA during initial (day 1-3) but not later phase (day 4-5) of morphine treatment. CGRP-immunoreactivity in DRG neurons, however, was increased in the later phase of morphine treatment. Naloxone challenge to morphine-treated animals precipitated an intense withdrawal syndrome that depleted CGRP-immunoreactivity and increased Fos expression in the dorsal horn. The Fos-response primarily occurred in neurons that expressed CGRP receptor component protein (RCP) suggesting CGRP activity contributes to neuronal activation during precipitated withdrawal. Spinal slices obtained from morphine-treated animals showed higher levels of CGRP release than from saline controls. Intrathecal co-administration of CB1-receptor antagonists, AM-251 or SR141716A, with daily morphine attenuated the behavioral manifestations of withdrawal. Treatment with AM-251 also reduced the depletion of CGRP, suppressed Fos-induction, and prevented the increase in capsaicin-evoked spinal CGRP release. Altogether, this study suggests that endocannabinoid activity, expressed via CB1-receptors, contributes to the induction of opioid physical dependence through spinal modulation of CGRP.

Animals↗
PubMed2001

Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors.

We report a type of synaptic modulation that involves retrograde signaling from postsynaptic metabotropic glutamate receptors (mGluRs) to presynaptic cannabinoid receptors. Activation of mGluR subtype 1 (mGluR1) expressed in cerebellar Purkinje cells (PCs) reduced neurotransmitter release from excitatory climbing fibers. This required activation of G proteins but not Ca2+ elevation in postsynaptic PCs. This effect was occluded by a cannabinoid agonist and totally abolished by cannabinoid antagonists. Depolarization-induced Ca2+ transients in PCs also caused cannabinoid receptor-mediated presynaptic inhibition. Thus, endocannabinoid production in PCs can be initiated by two distinct stimuli. Activation of mGluR1 by repetitive stimulation of parallel fibers, the other excitatory input to PCs, caused transient cannabinoid receptor-mediated depression of climbing fiber input. Our data highlight a signaling mechanism whereby activation of postsynaptic mGluR retrogradely influences presynaptic functions via endocannabinoid system.

Animals↗
PubMed2006

Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength.

The CB1 cannabinoid receptor has attracted much recent interest because of the observation that CB1 receptor antagonists have efficacy in treating metabolic syndrome and obesity. CB1 receptors also mediate most of the psychotropic effects of Delta9-tetrahydrocannabinol (Delta9THC), the principal psychoactive component of cannabis. In addition, they are one component of an interesting and widespread paracrine signaling system, the endocannabinoid system. The endocannabinoid system is comprised of cannabinoid receptors, endogenous cannabinoids, and the metabolic pathways responsible for their synthesis and degradation. The details of the endocannabinoid system have been most thoroughly studied in the brain. Here it has been shown to be intimately involved in several forms of neuronal plasticity. That is, activation of CB1 receptors by endocannabinoids produces either short- or long-term changes in the efficacy of synaptic transmission. The behavioral consequences of these changes are many, but some of the most striking and relevant to the current symposium are those associated with endogenous reward and consumptive behavior.

Appetite Regulation↗
PubMed2005

CB1 cannabinoid receptor-mediated modulation of food intake in mice.

1 Marijuana's appetite-increasing effects have long been known. Recent research suggests that the CB(1) cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB(1) cannabinoid receptors in the pharmacological effects of cannabinoids on food intake. 2 Mice were food-restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB(1) antagonist SR141716A dose-dependently decreased food consumption at doses that did not affect motor activity, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased food consumption at doses that had no effect on motor activity. O-3259 and O-3257, structural analogs of SR141716A, produced effects similar to those of the parent compound. 3 Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB(2) cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity. 4 SR141716A decreased feeding in wild-type mice, but lacked pharmacological activity in CB(1) knockout mice; however, basal food intake was lower in CB(1) knockout mice. Amphetamine decreased feeding in both mouse genotypes. 5 These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB(1) receptors may play a role in regulation of feeding behavior.

Animals↗
PubMed1994

Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids.

[3H]CP-55,940, a high-affinity cannabinoid receptor ligand, was used for in vitro binding and autoradiography in peripheral tissues in the rat. Specific cannabinoid receptor binding was found to be restricted to components of the immune system, i.e., spleen, lymph nodes and Peyer's patches. Displacement studies showed that this binding is identical (similar Kd and structure-activity profile) to that in brain. Cannabinoid receptors in the immune system are confined to B lymphocyte-enriched areas, i.e., the marginal zone of the spleen, cortex of the lymph nodes and nodular corona of Peyer's patches. Specific binding is absent in T lymphocyte-enriched areas, such as the thymus and periarteriolar lymphatic sheaths of the spleen. Certain macrophage-enriched areas, i.e., liver and lung, lack specific binding. Thus, the single peripheral cell type that may contain cannabinoid receptors is the B lymphocyte. Numerous sites have dense binding that could not be displaced by excess unlabeled drug. These nonspecific sites were found in the liver, adrenal glands and sebaceous glands, which are high in fat content, and in the heart, pancreas, components of the male and female reproductive systems and the epithelium of the esophagus. Thus, the highly lipophilic nature of cannabinoids does not appear to be the sole determinant of nonspecific binding. The data suggest that cannabinoids may exert specific receptor-mediated actions on the immune system of rats. Perhaps, also at high concentrations, cannabinoids exert membrane effects at sites where they are sequestered nonspecifically.

Adjuvants, Immunologic↗
PubMed2000

Cannabinoid receptors and the regulation of immune response.

Cannabinoid research underwent a tremendous increase during the last 10 years. This progress was made possible by the discovery of cannabinoid receptors and the endogenous ligands for these receptors. Cannabinoid research is developing in two major directions: neurobehavioral properties of cannabinoids and the impact of cannabinoids on the immune system. Recent studies characterized the cannabinoid-induced response as a very complex process because of the involvement of multiple signalling pathways linked to cannabinoid receptors or effects elicited by cannabinoids without receptor participation. The objective of this review is to present this complexity as it applies to immune response. The functional properties of cannabinoid receptors, signalling pathways linked to cannabinoid receptors and the modulation of immune response by cannabinoid receptor ligands are discussed. Special attention is given to 'endocannabinoids' as immunomodulatory molecules.

Animals↗